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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #330496

Research Project: Developmental Determinants of Obesity in Infants and Children

Location: Children's Nutrition Research Center

Title: Neuronal deletion of ghrelin receptor almost completely prevents diet-induced obesity

Author
item LEE, JONG HAN - Children'S Nutrition Research Center (CNRC)
item LIN, LIGEN - Children'S Nutrition Research Center (CNRC)
item XU, PINGWEN - Children'S Nutrition Research Center (CNRC)
item SAITO, KENJI - Children'S Nutrition Research Center (CNRC)
item WEI, QIONG - Children'S Nutrition Research Center (CNRC)
item MEADOWS, ADELINA - Children'S Nutrition Research Center (CNRC)
item BONGMBA, ODELIA Y. - Children'S Nutrition Research Center (CNRC)
item PRADHAN, GEETALI - Children'S Nutrition Research Center (CNRC)
item ZHENG, HUI - Baylor College Of Medicine
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/28/2016
Publication Date: 5/1/2016
Citation: Lee, J., Lin, L., Xu, P., Saito, K., Wei, Q., Meadows, A.G., Bongmba, O.N., Pradhan, G., Zheng, H., Xu, Y., Sun, Y. 2016. Neuronal deletion of ghrelin receptor almost completely prevents diet-induced obesity. Diabetes. 65:1-10. doi:10.2337/db15-1587.

Interpretive Summary: Ghrelin signaling has major effects on energy metabolism and glucose control, but it is unknown whether ghrelin's functions are taking place in the brain or in the peripheral tissues. The ghrelin receptor, Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in brain and detectable in some peripheral tissues. To understand the roles of neuronal GHS-R, we generated a mouse line where the Ghsr gene is deleted in all neurons. Our data showed that neuronal Ghsr deletion almost completely prevented diet-induced obesity (DIO) and significantly improved insulin sensitivity. The gene expression analysis suggested that hypothalamus and/or midbrain might be the sites that mediate the effects of GHS-R in thermogenesis and physical activity, respectively. Collectively, our results indicate that neuronal GHS-R is a crucial regulator of energy metabolism and a key mediator of DIO. These novel findings suggest that suppressing central ghrelin signaling may serve as a unique anti-obesity strategy.

Technical Abstract: Ghrelin signaling has major effects on energy- and glucose-homeostasis, but it is unknown whether ghrelin's functions are centrally and/or peripherally mediated. The ghrelin receptor, Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in brain and detectable in some peripheral tissues. To understand the roles of neuronal GHS-R, we generated a mouse line where Ghsr gene is deleted in all neurons using Synapsin 1-Cre driver. Our data showed that neuronal Ghsr deletion abolishes ghrelin-induced spontaneous food intake, but has no effect on total energy intake. Remarkably, neuronal Ghsr deletion almost completely prevented diet-induced obesity (DIO) and significantly improved insulin sensitivity. The neuronal Ghsr deleted mice also showed improved metabolic flexibility, indicative of better adaption to different fuels. In addition, gene expression analysis suggested that hypothalamus and/or midbrain might be the sites that mediate the effects of GHS-R in thermogenesis and physical activity, respectively. Collectively, our results indicate that neuronal GHS-R is a crucial regulator of energy metabolism and a key mediator of DIO. Neuronal Ghsr deletion protects against DIO by regulating energy expenditure, not by energy intake. These novel findings suggest that suppressing central ghrelin signaling may serve as a unique anti-obesity strategy.